Abstract Chronic long-term abuse of alcohol leads to myocardial dysfunction and results in heart failure. The mechanism by which alcohol causes cardiac damage remains unclear. Mitochondrial dysfunction plays a significant role in the development and complications of alcoholic cardiomyopathy due to changes in cellular lipid levels. In cell culture models, elevated lysophosphatidic acid (LPA) signaling induces markers of cardiomyocyte dysfunction (enhanced Atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP] expression). Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that heavy alcohol consumption enhances the myocardial autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. We speculate that upon heavy alcohol consumption, the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) bind to the autotaxin promoter and induce its expression. Furthermore, alcohol transactivates microRNA-92a, which is a negative regulator of LPP3. Thus, we hypothesize that heavy alcohol consumption alters autotaxin and LPP3 expression to drive lysophosphatidic acid signaling and myocardial dysfunction. The following interrelated specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific Aim 1 will assess the role of alcohol-induced autotaxin expression and lysophosphatidic acid production in the myocardium. Specific Aim 2 will determine the role of alcohol- mediated LPP3 depletion and lysophosphatidic acid regulation in the myocardium. We could identify whether modulation of extracellular versus intracellular antioxidant status confers a differential protective effect upon exposure to heavy alcohol consumption. This study will not only extend our understanding of alcohol- autotaxin-LPA-LPP3 mediated cardiac failure but will also identify novel targets for future clinical interventions.